Antibodies that are able to catalyze the antigen for which they are specific are produced spontaneously by the immune system. Catalytic immunoglobulins (Igs) both of the IgM and IgG isotypes have been detected in the serum of healthy donors, where they have been proposed to participate in the removal of metabolic waste and in the defense of the organism against invading pathogens. Conversely, antigen-specific hydrolytic IgG have been reported in a number of inflammatory, autoimmune and neoplastic disorders: their pathogenic effects have been demonstrated occasionally. The pathophysiological relevance of catalytic antibodies thus remains an elusive issue. Through the description of the pro-coagulation factor VIII as a model target antigen for catalytic antibodies, we propose that catalytic antibodies have either a beneficial or a deleterious role depending on the physiopathological context. Physiology thus relies on a delicate equilibrium between the levels of soluble target antigen and that of antigen-specific hydrolyzing immunoglobulins. Indeed, in patients with hemophilia A, in whom endogenous factor VIII is deficient or missing and exogenous factor VIII needs to be administered to treat hemorrhagic events, the development of factor VIII-hydrolyzing IgG that inactivate the therapeutically administered factor VIII, may reveal deleterious. In contrast, in a situation in which excess factor VIII may be detrimental and lead to excessive coagulation, disseminated thrombosis and organ ischemia, as seen in severe sepsis, our recent data suggest that the presence of factor VIII-hydrolyzing IgG may be beneficial to the patient.